James H. Flory

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ∼550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Common variants at five new loci associated with early-onset inflammatory bowel disease

The inflammatory bowel diseases (IBD) Crohns disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohns disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Variants of DENND1B Associated with Asthma in Children

BACKGROUND Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected]. CONCLUSIONS We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Strong synaptic transmission impact by copy number variations in schizophrenia

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 × 10−7). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

Duplication of the SLIT3 Locus on 5q35.1 Predisposes to Major Depressive Disorder

Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.1, harboring the SLIT3 gene (P = 2×10−3). Extending the controls with 30,000 subjects typed on the Illumina 550 k array, we found the CNV to remain exclusive to MDD cases (P = 3.2×10−9). Duplication was observed in 5 unrelated MDD cases encompassing 646 kb with highly similar breakpoints. SLIT3 is integral to repulsive axon guidance based on binding to Roundabout receptors. Duplication of 5q35.1 is a highly penetrant variation accounting for 0.7% of the subset of 647 cases harboring large CNVs, using a threshold of a minimum of 10 SNPs and 100 kb. This study leverages a large dataset of MDD cases and controls for the analysis of CNVs with matched platform and ethnicity. SLIT3 duplication is a novel association which explains a definitive proportion of the largely unknown etiology of MDD.

Effects of L-carnitine on dialysis-related hypotension and muscle cramps: a meta-analysis.

BACKGROUND L-Carnitine is an endogenous compound thought to be helpful in treating patients with dialysis-related hypotension and muscle cramps; however, sufficient evidence for these indications is lacking. STUDY DESIGN Systematic review and meta-analysis. SETTING & POPULATION Adult patients with end-stage renal disease receiving long-term hemodialysis. SELECTION CRITERIA FOR STUDIES All published English-language reports of randomized placebo-controlled trials of L-carnitine supplementation in adult long-term hemodialysis patients. INTERVENTION Supplemental L-carnitine (or placebo) for at least 8 weeks. OUTCOME Random-effects pooled odds ratio for intradialytic cramping or hypotension in L-carnitine-treated participants. RESULTS Of 317 potentially relevant articles, 7 (total enrollment of 193 patients) met criteria for inclusion. Four articles reported results for both hypotension and cramps, 1 had results for only hypotension, and 2 reported results for only cramps. Using data from all 6 relevant trials, the pooled odds ratio for cramping after L-carnitine supplementation was 0.30 (95% confidence interval, 0.09 to 1.00; P = 0.05). Analysis of the 5 studies examining the response of intradialytic hypotension to l-carnitine supplementation yielded a pooled odds ratio of 0.28 (95% confidence interval, 0.04 to 2.23; P = 0.2). LIMITATIONS The small number of available studies yielded limited statistical power. In addition, there was considerable interstudy heterogeneity. CONCLUSIONS Although suggestive in the case of muscle cramping, the available evidence does not confirm a beneficial effect of L-carnitine supplementation on dialysis-related muscle cramping or intradialytic hypotension. Additional study in the form of large rigorous randomized trials is needed in both cases.

Antidiabetic Action of Bezafibrate in a Large Observational Database

OBJECTIVE The purpose of this study was to test the hypothesis that bezafibrate, an approved fibrate, can prevent or delay type 2 diabetes. RESEARCH DESIGN AND METHODS This was a retrospective cohort study using data from routine medical practice in the U.K., as captured by the General Practice Research Database (GPRD). Individuals chronically exposed to bezafibrate were compared with individuals chronically exposed to other fibrates. Hazard ratios (HRs) for incident type 2 diabetes were calculated using a Cox proportional hazards model. A post hoc analysis was used to examine the effect of bezafibrate on progression to use of oral antidiabetic medications or insulin in individuals with diabetes at baseline. RESULTS Bezafibrate users had a lower hazard for incident diabetes than users of other fibrates (HR 0.66 [95% CI 0.53–0.81]). This effect became stronger with increasing duration of therapy. Post hoc analysis of the effect of bezafibrate on progression of preexisting diabetes also showed a lower hazard for progression to use of antidiabetic medication (0.54 [0.38–0.76]) or progression to use of insulin (0.78 [0.55–1.10]). CONCLUSIONS Bezafibrate appears to have clinically important antidiabetic properties. Randomized controlled trials should be considered to assess the utility of bezafibrate in treating patients with diabetes or in preventing diabetes in high-risk patients.

Metformin use reduction in mild to moderate renal impairment: possible inappropriate curbing of use based on food and drug administration contraindications.

assignments, as those close together were still poorly correlated. More likely, physicians were taking into account variables not contained in the MEWS, in assigning a PAR score. We conclude that the combined use of PAR and MEWS is more accurate than MEWS alone. A generalizable way to incorporate clinical judgment into aggregated weighted scoring systems on the wards may improve detection of clinical deterioration and assist with timely mobilization of resources to address the etiology of clinical deterioration.

Pharmacoepidemiologic Methods for Studying the Health Effects of Drug–Drug Interactions

A drug‐drug interaction (DDI) occurs when one or more drugs affect the pharmacokinetics (the bodys effect on the drug) and/or pharmacodynamics (the drugs effect on the body) of one or more other drugs. Pharmacoepidemiologic studies are the principal way of studying the health effects of potential DDIs. This article discusses aspects of pharmacoepidemiologic research designs that are particularly salient to the design and interpretation of pharmacoepidemiologic studies of DDIs.